Multiple cytokines including IL-2, IL-15, IL-12, and IL-18 alone and in combination enhance NK cell cytotoxicity and IFN-?? production. These and other cytokines can affect the accumulation and/or function of the apoptosis-associated Bcl-2 family of proteins. Currently the IL-2 family of cytokines is one of the best characterized regulators of Bcl-2 proteins. For example, IL-2 and IL-7 upregulate the expression of the pro-survival factor, Bcl-2 ((37)). Additionally, IL-7 causes phosphorylation of the BH3-only protein BAD to inhibit its proapoptotic activity ((38)). We have observed upon Western blot analysis that the IL-2 family of cytokines promotes a dramatic loss of the Bid protein in primary human NK cells. Loss of this protein would be expected to enhance survival of NK cells. Thus, it is our hypothesis that NK survival and function are regulated through cytokine regulation of BID. To address this hypothesis, we have accomplished the following:a. determined the molecular mechanisms responsible for cytokine regulation of Bid. We have found that Bid is controlled at the level of protein expression.b. analyzed if Bid expression is altered in human NK and T cell leukemias. We have found that a subset of cells from these malignancies are deficient in bid expression.c. determine if restoration of Bid expression can lead to changes in the sensitivity of primary NK cells as well as NK and T cell leukemias to apoptotic signals. We have observed that treatmenht with proteosome inhibitors restores Bid protein expression and correlates with the induction of apoptosis. The data we have generated thus far strongly suggests that analysis of Bid expression may provide new insight into the maturation of normal NK cells and the development of NK related malignancies.